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Gli immunomodulanti: il meccanismo d’azione
Giovanni A. Rossi
U.O. di Pneumologia e Allergologia
I.R.C.C.S. G. Gaslini, Genova
Fondazione
Gerolamo
Gaslini
Istituto
Giannina
Gaslini
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Biological Response Modifiers
• Prodotti dall’organismo: Lattoferrina
• Di derivazione vegetale: Echinacea, Propoli e
Resveratrolo
• Di derivazione batterica: Lisati batterici, Frazioni
antigeniche, Frazioni ribosomiali e Glicoproteine
• Di produzione sintetica: Levamisolo, Isoprinosina e
Pidotimod
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Lattoferrina
• L'affinità dei suoi domini cationici (+) per la superficie cellulare batterica, che ha una carica
(-), determina la morte del microrganismo per
citolisi
• La sua attività antimicrobica è correlata alla affinità per il Fe3+: sottraendo Fe3+ presente nelle secrezioni mucose, impedisce la proliferazione di virus, batteri e miceti
• E’ una proteina presente nel latte, nel colostro, nelle lacrime e nella saliva ma anche nei granuli specifici dei neutrofili
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Propoli
• E’ una sostanza resinosa che le api raccolgono dalle gemme e dalla corteccia delle piante ed elaborano aggiungendo pollini, cera ed enzimi prodotti dalle api stesse
• Contiene oltre 150 componenti tra le quali: a) Minerali: Mg, Ca, I, K, Na, Cu, Zn, Mn e Fe b) Vitamine: B1, B2, B6, C e E c) Enzimi: G6PD, fosfatasi acida d) Acidi: a. salicilico, a. caffeico, a. p-cumarico, a. grassi f) Alcoli: alcol benzilico, alcol cinnamilico. g) Flavonoidi e Terpeni
• La composizione della propoli è variabile a seconda della zona di origine, della stagione, dell’annata, etc …
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Resveratrolo
• Rinvenuto nella buccia dell'acino d'uva, è una delle fitoalessine prodotte naturalmente da parecchie piante, in difesa da agenti patogeni quali batteri o funghi
• Nel corpo umano il resveratrolo viene eliminato in brevissimo tempo ma si ha una scarsa conoscenza degli effetti collaterali della somministrazione prolungata di tale sostanza …….
• Possiede proprietà: antiossidanti, antinfiammatorie e antiaggreganti, legate alla capacità di bloccare la produzione della cicloossigenasi–2 (COX-2)
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Echinacea o “Cone flower”
• L‘Echinea è una pianta utilizzata anticamente dagli Indiani del Nord America per medicare molte malattie cutanee e le reazioni locali da morso di serpente
• La radice contiene numerose sostanze attive: a) poliacetileni e un glucoside (l’echinacoside), dotati di un marcato effetto antibiotico e fungicida b) oli essenziali ad azione immunostimolante
• Le indicazioni cliniche sono: a) uso topico nelle infiammazioni cutanee e nelle ferite torpide b) uso sistemico nella profilassi e il trattamento delle malattie da raffreddamento
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Major immunostimulant categories commonly used in childhood recurrent respiratory infections
• Bacterial extracts
• Synthetic chemical compounds
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Staphylococcus aureus, Streptococcus mitis, Streptococcus pyogenes, Streptococcus pneumoniae, Klebsiella pneumoniae, Moraxella catarrhalis, Haemophilus influenzae
Streptococcus pneumoniae, Streptococcus pyogenes, Klebsiella pneumoniae, Haemophilus influenzae
Oral bacterial extracts: mechanisms of action
Ribosomal extract
D53
Immucytal
RU41740 K. pneumoniae
Biostim
Glycoprotein
Increases Fc- receptor dependent phagocytosis Enhances the oxidative metabolism Inhibits of PMN migration
Increases complement- and Fc receptor-dependent phagocytosis Enhances the oxidative metabolism Does not affect neutrophil migration
Bacterial extracts LW50029
IRS-19
OM-85 BV Bronchovaxom
Lantigen B
Induces lymphocyte proliferation in MALT Increases IFN synthesis Enhances Th1 immune response Increases secretory IgA synthesis Activates macrophages and NK cells
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Activity of the oral bacterial extracts
TLR
Bacterial extracts
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Synthetic immunostimulants: mechanisms of action
An energy molecule, participating in O2 metabolism and protein synthesis
Stimulates macrophage activity Stimulates T- and B-cell proliferation and maturation
Isoprinosine A nucleoside
precursor to adenosine
Stimulates T-lymphocytes Restores the phagocitic activity of macrophages and PMNs
Levamisole A compound belonging
to imidazothiazole derivatives
Withdrawn from the market due to the risk of serious side effects
Synthetic dipeptide active on both the adaptive and the innate immune responses
Pidotimod 1,3-thiazolidine-4-
carboxylic acid
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Biological response modifiers
Caravaggio. L'incredulità di San Tommaso
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Immunostimulants for preventing respiratory tract infection in children
• Objectives. To determine the efficacy and safety of
immunostimulants in preventing acute respiratory tract
infections (ARTIs) in children
Del-Rio-Navarro BE, Espinosa-Rosales FJ, Flenady V, Sienra-Monge JJL The Cochrane Library 2008, Issue 4, 1-65
• Conclusions. This review showed that immunostimulants
reduce the incidence of ARTIs in children, by 40% on average
• The safety profile of immunostimulants appears to be good
• This positive result should be interpreted with caution due to
the heterogeneity and the poor quality of the trials
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The synthetic route assures purity and reproducibility of production process
Pidotimod
The spectrum of the different batches looks always the same
Bacterial extracts
The same does not occur with bacterial extracts
N
H
C O
S
COOH
N
Pidotimod
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Questions
• Is biodegradation occurring in
GE tract?
• Do we have convincing in vitro
and experimental animal studies
• Which new studies are needed?
N
H
C O
S
COOH
N
Pidotimod
The spectrum of the different batches looks
always the same
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Mean plasma concentration–time curve of pidotimod in 20 male volunteers after a single
800 mg oral dose of pidotimod
Liquid chromatogram of plasma sample of a volunteer 0.5 h after oral administration of pidotimod 800 mg
Zhang Y. Journal of Chromatography 2009; 877: 2566–2570
3.0-8.0 mg/ml
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HLA-DR
CD83
CD86
Human dendritic cell activation induced by exposure to Pidotimod (1 μg/ml)
Giagulli C. International Immunopharmacology 2009; 9: 1366–1373
A.P.C.
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Human CD4 T-cell activation induced by exposure to Pidotimod (1 μg/ml)
Giagulli C. International Immunopharmacology 2009; 9: 1366–1373
T-cells
IFN-g
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Intranasal immunization with Pidotimod increases IFN-g
production by splenocytes and bone marrow B-cells and OVA-specific IgG production
OVA 50μg/ dose
Pidotimod (100μg/ dose)
PBS
Days 0, 14 and 21
Giagulli C. International Immunopharmacology 2009; 9: 1366–1373
Splenocytes
IFN-g
Bone marrow cells
IFN-g
IgG
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Critical role of the CD30 co-stimulatory molecule in the development of allergic asthma
B T
CD30 OVA
Polte T. JACI 2006;118:942-8
CD30
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Pidotimod (10 μg/ml) decreases the in vitro the PHA-induced expression of CD30 in peripheral blood mononuclear cells of
atopic asthmatic and normal children
Gourgiotis D. J Asthma 2004; 41: 285-7.
Po
siti
ve c
ells
(%
)
12.5
10.0
7.5
5.0
2.5
0
HLA-DR CD-30
Control
Polimod 0.007
N.S.
A. HLA-DR+ & CD-30+ cells
CD
30
po
siti
ve c
ells
(%
)
12.5
10.0
7.5
5.0
2.5
0
Control Pidotimod 10 mg/ml
Normal
Atopic 0.012
0.02
B. CD-30+ cells
CD30
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The enhanced IFN-g production induced by intranasal immunization with Pidotimod increases the cytotoxic
activity of splenocytes
OVA 50μg/ dose
Pidotimod (100μg/ dose)
PBS
Days 0, 14 and 21
Giagulli C. International Immunopharmacology 2009; 9: 1366–1373
Splenocytes
IFN-g
Cytotoxic activity of Splenocytes
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Which kind of new information is needed ?
Intracellular pathways involved
Innate - Adaptive Immune System
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Possible intracellular signaling pathways involved in pidotimod actions
Surface or Cytoplasmic Receptor
Nuclear Factor-kB activation
Cytokine/Chemokine production, Adhesion molecule expression, Reactive O2 species generation
Calcium (Ca2+) mobilization
Proliferation, Differentiation, Activation
& Reactive O2 species generation
MAPK extracellular signal-regulated kinase (ERK)-1/2 phosphorylation Cell proliferation,
differentiation & TJ protein disruption
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TNF-a
ERK ½ - dependent T. J. disassembly
The first preliminary answer from HBECs ? IL-4, IFN-g, TNF-a
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Pro-inflammatory cytokines disrupt airway epithelial tight junctions Occludine and ZO-1
Petecchia L. Laboratory Investigation 2012 (in press)
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Cytokine-induced T. J. disruption is associated with reduction of airway epithelial barrier integrity
Petecchia L. Laboratory Investigation 2012 (in press)
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Inhibition of ERK-1 phosphorilation prevents cytokine-induced T. J. disruption
Petecchia L. Laboratory Investigation 2012 (in press)
ZO-1
Occlud
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Petecchia L. Laboratory Investigation 2012 (in press)
Inihibition of ERK-1 phosphorilation prevents cytokine-induced T. J. disruption
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Pidotimod and “constitutive” ERK ½ phosphorilation in airway epithelial cells
P-ERK 1/2
Tot-ERK 1/2
42 kDa
42 kDa
P-E
RK
1/t
ota
l ER
K r
atio
1.5 -
-
1.0 -
-
0.5 -
-
0.0 -
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Pidotimod and TNF-a-induced ERK ½ phosphorilation in airway epithelial cells
P-ERK 1/2
Tot-ERK 1/2
42 kDa
42 kDa
CTR 5’ 30’ 1h TNF-a 5’ 30’ 1h
Medium Pidot 100mg TNF-a Pidot 100mg +TNF-a
P-E
RK
1/t
ota
l ER
K r
atio
0.75 -
-
0.50 -
-
0.25 -
-
0.0 - CTR 5’ 30’ 1h TNF-a 5’ 30’ 1h Pidot 100mg Pidot 100mg+TNF-a
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Grazie per l’attenzione e … non mancate il 21-23 Giugno!
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Pidotimod and “constitutive” and TNF-a-induced ICAM-1 expression by airway epithelial cells
8000
6000
4000
2000
0
IC
AM
-1 e
xp
ressio
n (
MF
C)
CTR TNF-a 1 10 100
10 (ng/ml) Pidotimod (mg/ml)
IC
AM
-1 e
xp
ressio
n (
MF
C)
--- Pidotimod
TNF-a 10 (ng/ml)
8000
6000
4000
2000
0
1 (mg/ml
10 (mg/ml)
100 (mg/ml)
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IFN-g
Pidotimod induces a time-dependent modulation of ERK1/2 phosphorylation
ERK ½ - dependent T.J. lesion
The first preliminary answer from HBECs ?
IFN-g Quantitative evaluation of the effects of Pidotimod on ERK1/2 phosphorylation
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Pidotimod (400 mg/day x 60 days) or placebo in 101 children (4.7+2.1 years) with recurrent URTI
Burgio GR. Arzneim Forsch Drug-Res 1994; 44: 1525-29.
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Pidotimod in the acute phase and in the follow-up of RTI severe enough to require antibiotic
treatment
Maintenance
period
• Pidotimod
400 mg o.d.
• Placebo
o.d.
60 days
Caramia G. Arzneim-Forsch/Drug Res.1994; 44: 1480-82
• Acute phase
of the URTI
• Pidotimod
400 mg b.i.d.
+ antibiotics
• Placebo b.i.d.
+ antibiotics
15 days
60 children
60 children
Evaluation
Evaluation
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Pidotimod in the acute phase and in the follow-up of URTI severe enough to require antibiotic treatment
Caramia G. Arzneim-Forsch/Drug Res.1994; 44: 1480-82
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Oral purified bacterial extract (OM-85 BV) in acute respiratory tract infections in childhood:
a systematic quantitative review
• Aim. To summarised the evidence on the effectiveness of the immunomodulator OM-85 BV in the prevention of ARTI in children
Steurer-Stey C. Eur J Pediatr 2007; 166: 365-76.
• RESULTS. 13 studies (2,721 patients) of low to moderate quality tested OM-85 BV, but patients and outcomes differed substantially, which impeded pooling results
• CONCLUSION. Evidence in favour of OM-85 BV in the prevention of
ARTI in children is weak
• There is a trend for fewer and shorter infections and a reduction of antibiotic use
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Which kind of new information is needed ?
“Modern” clinical studies Intracellular pathways
involved
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P-E
RK
1/t
ota
l ER
K r
atio
0.75 -
-
0.50 -
-
0.25 -
-
0.0 - CTR 5’ 30’ 1h TNF-a 5’ 30’ 1h Pidot 100mg Pidot 100mg+TNF-a
Pidotimod and TNF-a-induced ERK ½ phosphorilation in airway epithelial cells
P-ERK 1/2
Tot-ERK 1/2
42 kDa
42 kDa
CTR 5’ 30’ 1h TNF-a 5’ 30’ 1h
Medium Pidot 100mg TNF-a Pidot 100mg +TNF-a